Microvascular resistance reserve in the presence of functionally significant epicardial stenosis and changes after revascularization

Abstract In the presence of functionally significant epicardial lesions, microvascular resistance reserve (MRR) calculation needs incorporation of collateral flow. Coronary fractional flow reserve (FFR cor ) requiring coronary wedge pressure (P w ), which is an essential part of the true MRR calculation, is reportedly estimated by myocardial FFR (FFR myo ) not requiring P w measurement. We sought to find an equation to calculate MRR without the need for P w . Furthermore, we assessed changes in MRR after percutaneous coronary intervention (PCI). An equation to estimate FFR cor was developed from a cohort of 230 patients who underwent physiological measurements and PCI. Corrected MRR was calculated using this equation and compared with true MRR in 115 patients of the different set of the validation cohort. True MRR was calculated using FFR cor . FFR cor and FFR myo showed a strong linear relationship (r 2 = 0.86) and an equation was FFR cor = 1.36 × FFR myo – 0.34. This equation provided no significant difference between corrected MRR and true MRR in the validation cohort. Pre‐PCI lower coronary flow reserve and higher index of microcirculatory resistance were independent predictors of pre‐PCI decreased true MRR. True MRR significantly decreased after PCI. In conclusion, MRR can be accurately corrected using an equation for FFR cor estimation without P w .


| INTRODUCTION
Microvascular dysfunction has been increasingly acknowledged as a relevant cause of myocardial ischemia. (Camici et al., 2015;Camici & Crea, 2007;Crea et al., 2014) Nonetheless, limited practical tools are available to quantify coronary microvascular function, particularly in the presence of significant epicardial coronary artery stenosis. (Fearon et al., 2003;Kelshiker et al., 2022;Layland et al., 2013;Travieso et al., 2022). Recently, microvascular resistance reserve (MRR), as an index specific for the assessment of microcirculation, has been proposed. (de Bruyne et al., 2021) MRR has been reported to be independent of autoregulation and myocardial mass and an operator-independent measure of the absolute value of microvascular resistance reserve. (de Bruyne et al., 2021) The theoretical framework of MRR and its derivation by physiological measures have been presented. The authors indicated that MRR should be corrected in the presence of significant epicardial stenosis as described for the index of microcirculatory resistance (IMR) correction by Aarnoudse et al. and Yong et al. (Aarnoudse et al., 2004;Fearon et al., 2013) Epicardial stenosis and microvascular dysfunction may coexist. (Taqueti & Di Carli, 2018) Identification or discrimination of these factors relevant to myocardial ischemia is challenging but might contribute to tailored management and therapeutic strategy for patients with chronic coronary syndrome. Thus, we sought to derive the equation of linear regression from estimating coronary fractional flow reserve (FFR cor ) in the derivation cohort and to validate the derived method for corrected MRR values using calculated FFR cor and apparent value of MRR (MRR app ) in the different set of the validation cohort. We then compared these corrected MRR values with those corrected using Yong's equation,  if Yong's equation is valid for the correction of MRR. We also assessed the changes in MRR after percutaneous coronary intervention (PCI) in the combined study population of derivation and validation. We further evaluated pre-PCI cut-off values of true MRR corresponding to coronary flow reserve (CFR), IMR, and resistive reserve ratio (RRR) threshold values. Predictive factors for pre-PCI low true MRR values were also evaluated.

| Study design and patient population
The derivation cohort was chosen from our institutional PCI database (Figure 1). The age and sex-matched validation cohort was also identified from this database in the same fashion described below. The present analysis was performed in a post hoc manner. Two hundred and thirty patients of the derivation cohort were randomly chosen from the all-comers institutional elective PCI registry database enrolling our regular clinical population according to the following inclusion criteria: age >20 years old with chronic coronary syndrome and the detection of an identifiable, single de novo culprit lesion located in the proximal portion of a native coronary artery and symptomatic ischemia or objective ischemia according to non-invasive stress testing and/or fractional flow reserve (FFR) measurements. Exclusion criteria included angiographically significant left main disease, renal insufficiency with baseline serum creatinine level >1.5 mg/dL, cardiomyopathy, and congestive heart failure. All patients underwent FFR-guided PCI and pre-and post-PCI physiological assessments with accessible data quality. After PCI, we further excluded patients with periprocedural myocardial infarction as defined by the Fourth Universal Definition of Myocardial Infarction, (Thygesen et al., 2018) based on a blood sample taken an average of 20-24 h, symptoms, and other objective findings after PCI completion, because such events have been reported to affect post-PCI physiological measurements. (Silvain et al., 2021)  minor cardiac troponin elevation, without other manifestations required by definition mentioned above, were included in the final analysis. The age and sex-matched validation cohort of 115 patients was similarly identified from the institutional registry. A representative case undergoing FFR-guided PCI with pre-and post-PCI angiograms and physiological data are shown in Figure 2. This study was conducted in compliance with the institutional ethics committee guidelines and received its approval (TKGH #2022FY83). The present study also complied with the Declaration of Helsinki for the investigation of human beings, and all patients provided written informed consent before the institutional registry enrollment for future investigations. Prompt optimal medical therapy was initiated in all patients before PCI.

| Pre-and post-PCI physiological measurements and analysis
Coronary angiography and PCI procedure were performed by standard techniques. Coronary angiograms were analyzed quantitatively using a CMS-MEDIS system (Medis Medical Imaging Systems). The PCI techniques and imaging devices, such as intravascular ultrasound or optical coherence tomography, and stent type (drugeluting stent) were at the interventionalists' discretion. Pre-and post-PCI FFR, CFR, and IMR measurements were performed, as previously described. (de Bruyne et al., 2001;Fearon et al., 2003;Matsuda et al., 2016;Pijls et al., 1996) Briefly, coronary physiological measurements were obtained by a 6F guiding catheter via radial approach using a pressure-temperature sensor guidewire and analyzing systems (PressureWire X Guidewire, Abbott Laboratories, Il, USA, RadiAnalyzer, St, Jude Medical, St Paul, Minnesota, UAS and CoroFlow, Coroventis Research AB, Uppsala, Sweden). After the administration of a bolus of intracoronary nitrate (200 μg), the wire sensor was advanced and positioned as far distally in the target vessel as practical. Hyperemia was induced by infusion of adenosine or adenosine triphosphate into an antecubital vein at a rate of 140 μg/ kg/min or 160 μg/kg/min, respectively. FFR was calculated as the ratio of distal coronary pressure to proximal pressure at stable hyperemia. CFR was obtained using the thermodilution method as the ratio of resting transit time divided by hyperemic transit time (T mn ). IMR was calculated as the distal coronary pressure at maximal hyperemia divided by the inverse of the hyperemic T mn . RRR was calculated by CFR adjusted using the ratio between resting and hyperemic distal coronary pressure. (Lee et al., 2020) The P a , P d , and P w were recorded during balloon dilatation during PCI. Post-PCI physiological measurements were also performed in a similar manner after post-stenting high-pressure dilatation using a noncompliant balloon and/or additional stenting guided by physiological and intravascular imaging at the operators' discretion and when the operator considered as final as the PCI procedure.

MRR correction
As reported in the study by Yong et al., the regression formula between FFR cor and FFR myo of best fit by a straight line was obtained in the derivation cohort. This formula was tested in the validation cohort. MRR is defined as the ratio of true resting to hyperemic microvascular resistance (R μ ), as recently described. (de Bruyne et al., 2021) The theoretical framework of calculating resting R μ , hyperemic R μ , MRR, and the relationship between FFR, CFR, and MRR was shown by de Bruyne et al. (2021) Briefly, MRR is defined by the following equation: where P a, rest and P d, hyper are resting aortic and hyperemic distal coronary pressure, respectively, and Q rest and Q max are the resting and hyperemic absolute coronary blood flow. This equation can also be described using CFR and FFR by the following equation: where FFR indicates FFR myo . As suggested by De Bruyne et al., true MRR, in the presence of significant epicardial stenosis, should be derived by correcting MRR app and can be expressed by the following: where true MRR and MRR app represent corrected MRR and measured MRR, respectively. Consequently, using the formula of the relationship between FFR myo and FFR cor , we can obtain a corrected MRR. In the validation cohort, we also compared true MRR values with corrected MRR values using Yong's equation  if there is no statistically significant difference between these two values obtained by each of the two equations for FFR cor estimation. We summarized definitions of all physiological parameters below. We further assessed the changes in MRR values in the total cohort, including both derivation and validation cohorts (345 patients) after PCI.

| Derivation of the equation for FFR cor using FFR myo , and its validation
The formula to estimate FFR cor using FFR myo in the derivation cohort was obtained as follows: when ( Figure 3) this equation was applied in the validation cohort, no significant difference was detected between measured and calculated FFR cor (0.59 ± 0.14 vs. 0.59 ± 0.13, p = 0.661; Figure 4a), and good correlation was observed between these two variables (r 2 = 0.90, p < 0.001; Figure 4b,c). 4.04 ± 1.53, p = 0.187) was detected (Figure 5a). There was also a good correlation and agreement between these two variables (Figure 5b,c). As seen from the equation for FFR cor calculation, this equation is no more valid when FFR myo is equal to or less than 0.25 since the denominator is close to zero or a negative number. Corrected MRR was significantly higher than MRR app (4.04 ± 1.53 vs. 3.42 ± 1.35, p < 0.001). When MRR app was corrected using Yong's equation, Yong's equation-derived corrected MRR was significantly different from those corrected by our equation (3.99 ± 1.51 vs. 4.04 ± 1.53, p < 0.001) and also showed a significant difference from true MRR in the validation cohort (3.99 ± 1.51 vs. 4.13 ± 1.71, p = 0.046).

| Change in MRR and the relationship between MRR, CFR, and RRR after PCI
Post-PCI true MRR values significantly decreased (4.14 ± 1.78 vs. 3.70 ± 1.87, p < 0.001; Figure 6). Notably, a relatively low agreement was observed between preand post-PCI true MRR values when categorized by the best cut-off value corresponding to CFR values of 2.5 (kappa = 0.238). There remained a significant correlation between post-PCI true MRR and RRR (r 2 = 0.97, p < 0.001). Table 2 shows the univariate and multivariate logistic regression analyses to predict the target vessels with pre-PCI decreased true MRR (MRR < 4.08, threshold corresponding to CFR = 2.5). Pre-PCI higher IMR and lower CFR FFR cor = 1.36 × FFR myo − 0.34 r 2 = 0.86, p < 0.001 were independent predictors of the vessels with decreased pre-PCI true MRR.

| DISCUSSION
In this study, we first sought to derive the equation for estimating FFR cor without knowing P w , as shown in the study by Yong et al. (Yong et al., 2013)  corresponding to reported CFR, IMR, and RRR threshold values in the presence of functionally significant stenosis. We also evaluated the agreement of MRR for the assessment of microvascular dysfunction in comparison with IMR and between pre-and post-PCI MRR values. Finally, the changes in true MRR after uncomplicated PCI were assessed, and predictors of lower pre-PCI true MRR were explored.
The important findings of this study are as follows; (1) FFR cor can be accurately estimated by the equation as follows: FFR cor = 1.36 × FFR myo -0.34, showing better performance compared with Yong's formula; (2) in the presence of functionally significant stenosis, corrected MRR can be accurately calculated by the equation as follows: corrected MRR = MRR app × (FFR myo / FFR cor ) = (MRR app × FFR myo ) / (1.36 × FFR myo -0.34); (3) corrected MRR was significantly higher than MRR app ; (4) true MRR cut-off values in the presence of significant stenosis corresponding to CFR = 2.0 and 2.5 were 3.27 and 4.08, respectively; (5) true MRR cut-off values corresponding to IMR = 25 was 4.61; (6) true MRR cut-off value corresponding to RRR = 3.5 was 4.08; (7) true MRR values significantly decreased after PCI and were virtually identical with CFR, while agreement of true MRR before and after PCI was relatively low; (8) pre-PCI higher IMR values and lower CFR values were independent predictors of low pre-PCI true MRR. This is the first study that derived the equation for corrected MRR values in the presence of functionally significant stenosis and validated the equation in the different validation cohort. We also proposed true MRR cut-off values corresponding to reported CFR, IMR, and RRR cut-off values, respectively. Furthermore, we presented that the true MRR significantly decreased after uncomplicated PCI, although the agreement between pre-and post-PCI MRR was not high. Recent studies indicate that coronary microvascular dysfunction is a prevalent cause of myocardial ischemia and is associated with poor outcomes. Lee et al., 2016) Microvascular dysfunction is difficult to be visualized and may coexist with obstructive epicardial coronary disease, (Taqueti & Di Carli, 2018;Taqueti et al., 2015) contributing to myocardial ischemia. After successful PCI, preexisting coronary microvascular dysfunction (CMD) or altered microvascular function might emerge and impact the occurrence of ischemic symptoms or adverse events (Misawa et al., 2022;Sechtem et al., 2020;Taqueti et al., 2015) There has been limited data regarding the impact of CMD on prognosis in patients with obstructive epicardial coronary lesions or its behavior after elective PCI. MRR has recently been proposed by Bruyne et al., as defined as the ratio of true resting to hyperemic microvascular resistance. MRR should be corrected in the presence of significant epicardial disease. Our results indicated the wide distribution of MRR and relatively low agreement with IMR before PCI, suggesting that MRR might discriminate the extent of coexisting microvascular dysfunction (MVD) differently from IMR in the presence of significant obstructive disease, although further studies are needed. A strong linear correlation was observed between MRR and CFR. In contrast, a less robust relationship was detected between MRR and IMR, indicating that these two measures for MVD may complementarily provide clinical information about MVD, as suggested above. Further studies are needed to clarify if MRR may provide prognostic information independently of CFR, IMR, or RRR, and whether these indices could be used to discriminate or clarify the relative contribution of myocardial ischemia due to epicardial stenosis and MVD in the presence of significant epicardial disease. Our study provides the clinical characteristics of MRR and true MRR cut-off values corresponding to CFR, IMR, and RRR cut-off values to classify the relevance of MVD by these metrics by proposing the reference cut-off values of each index. Further investigations using these indices for elucidating the clinical significance of CMD in the presence of significant epicardial stenosis were warranted.

| LIMITATIONS
This study was a single-center retrospective analysis of registered patients' data and pertained to an observational nature; thus, its inherent limitation exists. Rigorous exclusion criteria and the protocol for inclusion limited the number of study patients and may have resulted in a certain level of further selection bias. In the report by Bruyne et al., absolute coronary flow and microvascular resistance measurements were performed using intracoronary continuous saline infusion method for the theoretical framework and MRR validation. In contrast, this study used the thermodilution method (de Bruyne et al., 2021) for CFR and IMR. Currently, both RayFlow® catheter (HEXACATH, Paris, France) and an 0.014" dual pressure and Doppler flow velocity sensor guidewire (ComboWire XT, Philips Volcano) are not commercially available in Japan.

| CONCLUSION
As proposed, without needing P w in the presence of significant epicardial stenosis, true MRR can be accurately calculated using calculated FFR cor and measured MRR. Pre-PCI lower CFR and higher IMR were independent predictors of pre-PCI decreased MRR. Proposed true MRR cut-off values corresponding to CFR and IMR thresholds representing microvascular dysfunction need to be validated in clinical studies. T A B L E 2 Univariate and multivariate logistic regression analysis for predicting pre-PCI decreased true MRR (MRR < 4.08).